New inotropic agents: Milrinone analogs

1. Two new milrinone analogs, 3-acetyl-6-phenyl-2(IH)-pyridone (SF 348) and 3-acetyl-7-methyl-7,8-dihydro-2,5(1H, 6H) quinolinone (SF 349), increase the contractile activity of spontaneously beating and electrically driven atria isolated from reserpine-treated guinea-pigs. 2. Propranolol 0.1 mu M drastically inhibits the contractile effect of SF 348, whereas that of SF 349 is unaffected. Preincubation of the atria with adenosine-deaminase suppresses the cardiac activity of SF 349, but does not affect that of SF 348. 3. SF 349 competitively antagonizes the negative inotropic effect induced by N-6-(R-phenylisopropyl)-adenosine (R-PIA) and displaces N-6-cyclohexyl[H-3]-adenosine (H-3-CHA) from its binding sites to A(1) receptors in the guinea-pig heart. 4. The positive inotropic effect of SF 348 is largely sustained by activation of beta-adrenoceptors, whereas SF 349 acts by displacing endogenous adenosine from its inhibitory (A(1)) receptors in the atria. (C) 1997 Elsevier Science Inc.